7/15/2019 Pharmacokinetics JEFFERY A. BENNETT B.SC., R.PH., PHARM.D. 1 Overview Pharmacokinetics examines the movement of a drug over time throughout the body. 4 Fundamental Pathways: 1. Drug absorption from the site of administration (input) permits entry of the therapeutic agent (either directly or indirectly) into plasma. 2. The drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids (distribution. 3. The drug may be metabolized by the liver, kidney, or other tissues. 4. The drug and its metabolites are eliminated from the body (output) in urine, bile, or feces. 2 1 7/15/2019 Routes of Drug Administration Primarily: Properties of the drug (for ex: water or lipid solubility, ionization, etc.) The therapeutic objectives (for ex: the desirability of a rapid onset of action or the need for long-term administration or restriction to a local site). Two major routes of drug administration: Enteral Parenteral 3 Enteral 1. Oral 2. Sublingual 3. Rectal 4 2 7/15/2019 Parenteral 1. Intravascular 2. Intramuscular (IM) 3. Subcutaneous (SC) 5 1. Inhalation 2. Intranasal 3. Intrathecal/Intraventricular 4. Topical 5. Transdermal 6 3 7/15/2019 Absorption of Drugs Absorption: the transfer of a drug from its site of administration to the bloodstream. The rate and efficiency of absorption depend on the rout of administration. For IV delivery, absorption is complete. Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. 7 Transport of a Drug from the GI Tract 1. Passive diffusion 2. Active transport 8 4 7/15/2019 Effect of pH on Drug Absorption Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a H+ causing anion (A-) to form 2 Weak bases (BH+) can also release a H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B). 1. Passage of an uncharged drug through a membrane. 2. Determination of how much drug will be found on either side of a membrane. 9 pH = pKa + log[nonprotonated species]/[protonated species] For Acids: pH = pKa + log [A-]/[HA] For Bases: pH = pKa + log [B]/[BH+] 10 5 7/15/2019 Physical Factors Influencing Absorption 1. Blood flow to the absorption site. 2. Total surface area available for absorption. 3. Contact time at the absorption surface. 11 Bioavailability Bioavailability is the fraction of administered drug that reaches the systemic circulation. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example: If 100mg of a drug is administered orally and 70mg of this drug is absorbed unchanged, the bioavailability is seventy percent. 12 6 7/15/2019 Drug Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on (1)blood flow, (2) capillary permeability, (3) the degree of binding of the drug to plasma and tissue proteins, and (4) the relative hydrophobicity of the drug. 13 Blood Flow The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs. 14 7 7/15/2019 Capillary Permeability Capillary Structure: Capillary structure varies widely in terms of fraction of the basement membrane that is exposed by slit junctions between endothelial cells. Blood-drain barrier: To enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported. 15 Drug Structure: The chemical nature of the drug strongly influences its ability to cross cell membranes. Hydrophobic drugs, which have a uniform distribution of electrons and no net charge, readily more across most biological membranes. These drugs can dissolve in the lipid membranes and, therefore, permeate the entire cell’s surface. The major factor influencing the hydrophobic drugs distribution is the blood flow to the area. By contrast, hydrophilic drugs which have wither a nonuniform distribution of electrons or a positive or negative charge, do not readily penetrate cell membranes and must go through the slit junctions. 16 8 7/15/2019 Binding of Drugs to Proteins Reversible binding to plasma proteins sequesters drugs in a non- diffusable form, and slows their transfer out of the vascular compartment. Plasma albumin is the major drug-binding protein, and may act as a drug reservoir. 17 Volume of Distribution A hypothetical volume of fluid into which a drug is disseminated. 18 9 7/15/2019 Water Compartments in the Body Once a drug enters the body, from whatever route of administration, it has the potential to distribute into any one of the three. Plasma Compartment: If a drug has a very large molecular weight or binds extensively to plasma proteins, it is too large to move out through the endothelial slit junctions of the capillaries and, thus, is effectively trapped within the plasma (vascular) compartment. As a consequence, the drug distributes in a volume (the plasma) that is about 6% of the body weight or, in a 70kg individual, about 4L of body fluid. Heparin shows this type of distribution. 19 Extracellular fluid: If a drug has a low molecular weight but is hydrophilic, it can move through the endothelial slit junctions of capillaries into the interstitial fluid. However, hydrophilic drugs cannot move across the membranes of cells to enter the water phase inside the cell. Therefore, these drugs distribute into a volume that is the sum of the plasma water and the interstitial fluid, which together constitute the extracellular fluid. This is about 20% of the body weight, or about 14L in a 70kg individual. Aminoglycoside antibiotics show this type of distribution. 20 10 7/15/2019 Total Body Water: If a drug has a low molecular weight and is hydrophobic, it not only can move into the interstitium through the slit junctions, but can also move through the cell membranes into the intracellular fluid. The drug therefore distributes into a volume of about 60% of body weight, or about 42L in a 70kg individual. Ethanol exhibits this apparent volume of distribution. 21 Binding of Drugs to Plasma Proteins Drug molecules may bind to plasma proteins (usually albumin). Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in the tissues. 22 11 7/15/2019 Binding Capacity of Albumin The binding of drugs to albumin is reversible. Albumin has the strongest affinity for anionic drugs (weak acids) and hydrophobic drugs. Most hydrophilic drugs and neutral drugs do not bind to albumin. 23 Drug Metabolism Drugs are most often eliminated by biotransformation and/or excretion into urine or bile. The liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues. [Note: Some agents are initially administered as inactive compounds.] 24 12 7/15/2019 Kinetics of Metabolism First-Order Kinetics: The metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis- Menten kinetics. V = rate of drug metabolism = Vmax[C]/Km In most clinical situations, the concentration of the drug, [C], is much less than Michaelis constant, Km and the Michaelis-Menten equation reduces to: V = rate of drug metabolism = Vmax[C]/Km That is, the rate of drug metabolism is directly proportional to the concentration of free drug, and first-order kinetics are observed. 25 Zero-Order Kinetics V = rate of drug metabolism = Vmax[C]/[C] = Vmax The enzyme is saturated by a high free-drug concentration, and the rate of metabolism remains constant over time. This is called zero- order kinetics (or sometimes referred to clinically as nonlinear kinetics). A constant amount of drug is metabolized per unit of time. 26 13 7/15/2019 Reactions of Drug Metabolism The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal tubules. Therefore, lipid-soluble agents must first be metabolized in the liver using two general sets of reactions, called Phase I and Phase II. 27 Phase I: Reactions function to convert lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group. Phase I reactions utilizing the P450 system: The phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system (also called microsomal mixed function oxidase). Drug + O2 + NADPH + H+ Drugmodified+H2O+NADP The oxidation proceeds by the drug binding to the oxidized form of cytochrome P450, and then oxygen is introduced through a reductive step coupled to NADPH: cytochrome P450 oxicderoeductase. 28 14 7/15/2019 Inducers: The cytochrome P450-dependent enzymes are an important target for pharmacokinetic drug interactions. One such interaction is the induction of selected CYP isozymes. Certain drugs, most notably phenobarbital, rifampin, and carbamazepine, are capable of increasing the synthesis of one or more CYP isozymes. The increased biotransformation rates can lead to significant decreases in plasma concentrations of drugs as measured by AUC, with concurrent loss of pharmacologic effect. 29 Inhibitors: Inhibition of CYP isozyme activity is an important source of drug interactions that leads to serious adverse events. The most common form of inhibition is through competition for the same isozyme. 30 15 7/15/2019 Phase II This phase consists of conjugation reactions. Glucuronidation is the most common and the most important conjugation reaction. 31 Drug Elimination Removal of a drug from the body may occur via a number of routes, the most important being through the kidney into the urine.